Cardiovascular disease treatment has evolved rapidly over the last few decades from the early diuretics and natural products such as rauwolfia serpentina to the newest agents such as angiotensin converting enzyme inhibitors (ACEI) of the last few years and the even more recent calcium channel blockers (CCB). In efforts to achieve improved therapy (primarily for the treatment of hypertension, its sequelae, reversible conditions secondary to hypertension, and hypertension secondary to other conditions), a number of agents in each of these classes have been tested both alone as well as in combination with other agents. Some of the conditions for which at least one of these agents has been used or is believed useful include, without limitation, hypertension, angina, myocardial infarction, atherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction, stroke, and headache. Others will be apparent to those of ordinary skill in the art based on a knowledge of the underlying mechanisms involved as well as on general clinical and pre-clinical experience.
Benazepril, benazeprilat, and their pharmaceutically acceptable salts are disclosed in U.S. Pat. No. 4,410,520, along with pharmaceutically acceptable dosage forms thereof, dosage ranges and suitable routes of administration therewith, and uses therefor, all of which are incorporated herein by reference. Amlodipine and its pharmaceutically acceptable salts are set forth in U.S. Pat. No. 4,572,909, incorporated herein by reference. Phamaceutically acceptable dosage forms, dosage ranges, suitable routes of administration, and uses of amlodipine and its salts are set out there. U.S. Pat. No. 4,879,303 is directed to the besylate salt of amlodipine, and it too is incorporated herein by reference. More specific dosages, routes of administration, formulations, and uses for amlodipine besylate can be found there. An excellant review of amlodipine is Burges et al, Cardiovas Drug Dev. 8(1) 25-44, 1990.
Recently, particular combinations of an ACEI and a CCB have appeared in the literature. See generally for example EP 334,264 A2 (corresponding to U.S. application Ser. No. 171,068, filed Mar. 21, 1988), EP 180,785-B and EP 257,485; J. Cardiovas. Pharm 1988, 12(5) p.600-607; J. Cardiovas. Pharm, 1988, 12, Suppl 6, p.S104-108 and Suppl 4, p.S80-85; and Diabetologia 1/89 32(1), p.40-44. More specific references which have appeared include: J. Hum. Hypertens. Aug 1988 2(2) p.127-132 and J. Cardiovas Pharmacol 1988 12 Suppl 7 p S85-88, each of which discloses combination usage of amlodipine with captopril; and Br. J. Clin. Pharmac. 1987, 24, 465-472, disclosing combination usage of benazepril and nicardipine; and J. Amer. Coll. Cardiol. 17 (2) 188A, 1991, disclosing combination usage of benazepril and nifedipine. In this last reference, the authors conclude that there is no advantage in combining benazepril and nifedipine over the use of nifedipine alone. Hence, the art has mixed teachings as to the benefits of combination therapy between ACEIs and CCBs generally, and especially with the use of benazepril as the ACEI in such combinations.